The dysfunction of BP180/collagen XVII in keratinocytes promotes melanoma progression

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Abstract

BP180, also termed collagen XVII, is a hemidesmosomal transmembrane glycoprotein expressed in basal keratinocytes, and functions as a cell–matrix adhesion molecule in the dermal–epidermal junction of the skin. Its function, other than cell–matrix adhesion, remains unclear. We generated a mouse strain with BP180 dysfunction (termed ∆NC16A), which develops spontaneous skin inflammation accompanied by an influx of myeloid derived suppressor cells (MDSCs). We used the B16 mouse melanoma model to demonstrate that BP180 dysfunction in either skin or basal keratinocytes promotes MDSC influx into skin and tumor progression. MDSC depletion reduced tumor progression in ∆NC16A mice, demonstrating a critical role for BP180 dysfunction-driven MDSCs in melanoma progression. This study provides the first direct evidence that BP180, a cell–cell matrix adhesion molecule, possesses antitumor function through modulating infiltration of MDSCs. Basal keratinocytes actively participate in skin microenvironment changes caused by BP180 dysfunction. ∆NC16A mice could be a new animal model to study the melanoma microenvironment.

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Acknowledgements

We thank Dr. Dennis Loop for providing the Krt-14 promoter driven Cre mice. We thank Dr. Donna Culton and Susan McCray for assistance in Flow Cytometry. We thank Dr. Yisong Wan and Dr. Jenny PY Ting for their assistance. We thank the UNC Flow Cytometry Core Facility, which is supported in part by P30 CA016086 Cancer Center Core Support Grant to the UNC Lineberger Comprehensive Cancer Center, for their assistance in flow cytometry analyses. This work was supported by the NIH (R01 AI40768 and R01 AR072694 to ZL), the 15 UNC Cancer Center Research Award (to ZL) and UNC Graduate School Dissertation 16 Completion Fellowship (to BJH) and P01CA206980 (to NT).

Authors contributions

Conception and design: BJH, MS, NL, ZL. Development of methodology: BJH, JB, SW. Acquisition of data (provided animals, acquired and managed patients, provided facilities, etc.): BJH, JB, ZL, JC, CCS, ZY. Analysis and interpretation of data (e.g., statistical analysis, biostatistics, computational analysis): BJH, JB, YS, MS, NL, NT, ZL. Writing, review, and/or revision of the manuscript: BJH, YS, ZY, JC, MS, NL, NT, ZL. Administrative, technical, or material support (i.e., reporting or organizing data, constructing databases): PG, SB, KL, YS, BJH. Study supervision: MS, NL, ZL.

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Correspondence to Zhi Liu.

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